Process for the production of beta-keto amides



United States Patent 3,136,223 PROCESS FOR THE PRODUCTION OF BETA-KETO AMIDES Walter F. Hotfstadt, Vestal, N.Y., assignor to General Aniline & Film Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed May 2, 1961, Ser. No. 107,035 11 Claims. (Cl. 260558) This invention pertains to a new process for preparing beta-keto amides, especially those of the aromatic and heterocyclic series. The invention also pertains to certain aromatic and heterocyclic beta-keto amides which have not been previously disclosed or described in the chemical literature.

Beta-keto amides, especially those belonging to the aromatic series, are valuable and important chemical intermediates and are extensively used in the dying and related arts. These compounds are particularly useful in the realm of color photography where they are employed as couplers for providing yellow dye images.

As is well known, modern color photography normally makes use of the color forming development reaction or principle for reproducing or recording the color aspects of the subject. In this system of color photography, three silver halide emulsion layers are coated in superimposition and each layer is sensitized to /3 of the visible electromagnetic spectrum, i.e., the red, green and blue regions respectively. On exposure and subsequent color development, the color aspects are recorded in the form of their subtractively colored primary images in each of the three sensitized layers. These images act as color filters which modulate the viewing light, resulting in a full color reproduction of the original subject matter.

In forming subtractively colored dye images by color development, a coupler or color forming component reacts with the oxidation product of the developing agent. It is the common practice to employ a phenolic or naphthol compound for producing a cyan image or the red aspects of the subject; a pyrazolone coupler to form a magenta image, or green aspects, and a beta-keto amide to reproduce the yellow image or blue aspects.

The beta-keto ester coupling component is prepared by reacting an aroylacetic ester with a primary aromatic amine such as aniline, whereby alcohol is eliminated with concomitant formation of the beta-keto amide. This reaction, which constitutes the only general method for arriving at beta-keto amide couplers, is a reliable reaction and normally provides good yields. Nevertheless, it suffers from one serious drawback. The requisite aroylbenzylacetic ester starting material is difiicult to obtain except for a few relatively simple derivatives.

Acyl-acetic esters including those of the aromatic type are notoriously diflicult and tedious compounds to prepare. Despite the vast and extensive research in color former chemistry, there is still no reliable and general method of synthesis for providing aroylacetic esters. That this is indeed the case is evident by making reference to Organic Reactions, volume 1, published by John Wiley and Sons, Inc., New York, New York, chapter 9, which consists of a comprehensive treatise on the synthetic methods which are available for producing beta-keto esters. With respect to aroyl-acetic esters, however, this reference, at page 297 (d), points out that al though a number of methods have been used for preparing beta-keto esters of this type, none appears to be an entirely satisfactory general method. Manifestly, such difiicultly accessible intermediates have made it difficult or impossible to arrive at many new and potentially valuable beta-keto amide structures for use as couplers in producing yellow photographic images.

I have now discovered a new method for preparing 3,130,228 Patented Apr. 21, 1964 beta-keto amides which completely eliminates the need for aroylacetic esters, the scarcity of which has heretofore hindered the development of many valuable photographic couplers, and the provision of the aforementioned method for preparing beta-keto amide couplers constitutes the objects and purposes of this invention.

Other objects and purposes will become apparent as the description proceeds.

I have discovered that beta-keto amides can readily be produced by reacting a methylarylketone with an arylisocyanate or the urethane derivatives thereof in the presence of a strongly basic condensing agent, a reaction which yields directly the basic salt of the beta-keto amide. Acidification of the coupler salt gives the free beta-keto amide.

Although I have not determined the exact mechanism, it is my opinion that the course of reaction proceeds as indicated in the following equations:

0 02 5 RlNHtiloc H NaOOH; R N=C OH OH ONa OC2H5 0 R1N=C 5H- CH gR ONa ONa

In the equations as above depicted, -I have ascertained that the reaction proceeds generally when R and R are aromatic or heterocyclic rings. The only limitation which I have been able to attribute to the new method of synthesis hinges on the availability of the starting materials, that is, the arylisocyanate or urethane thereof and methylarylketone. Since these compounds exist in the form of numerous derivatives, manifestly, the reaction is of Wide scope and applicability.

The beta-keto amides prepared in accordance with my invention can be depicted formulistically as follows:

wherein R and R each represents an aromatic nucleus such as phenyl, cyanophenyl, aminophenyl, halophenyl, e.g., chlorophenyl, dichlorophenyl, trichlorophenyl, fluorophenyl, bromophenyl, etc., hydroxyphenyl, alkoxyphenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, hexoxyphenyl, decoxyphenyl, heptoxyphenyl, decoxyphenyl, undecoxyphenyl, pentadecoxyphenyl, heptodecoxyphenyl, etc., alkylphenyl, e.g., methylphenyl, ethylphenyl, propylphenyl, butylphenyl, amylphenyl, heptylphenyl, octylphenyl, undecylphenyl, tetradecylphenyl, pentadecylphenyl, octadecylphenyl, etc., naphthyl, al kylnaphthyl, wherein the alkyl is the same as above in alkylphenyl halonaphthyl, e.g., chloronaphthyl, bromo naphthyl, etc., alkoxylnaphthyl, wherein the alkyl is the same as above in alkoxylphenyl; a heterocyclic nucleus such as thiazolyl, methylthiazolyl, thienyl, furyl, benzothiazolyl, pyridyl, quinolyl, quinoxalinyl and the like.

Beta-keto amide couplers falling within the ambit of formula can be illustrated as follows:

EtO

As the source of the aroyl grouping in the above described compounds, I use various methyl aromatic and heterocyclic ketones of the type illustrated by the following formula:

wherein R has the significance as defined in Formula I. Exemplary methyl ketones falling within the scope of Formula I include the following:

OCH3

OOCH

COOH3 000153 COCH3 C1 OH Cm m C 0 CH3 0 0 CH 2 Me H3C(|]-CH COCH3 COCH3 HO- M60 COCH;

COCH:

ll le COGH M Me

00GB; COOH; COOH;

I EI:

COCH

00011 COOH (i)M Me0 COCH3 OMe @o o 011 I OMe MeO

I OMe [ID-O 0 CH3 -0 0 OH; I

Br J-oo OH I I \O 0 014 20 0 Ca n OH :c-rx S I CHJLN/H Cl i COCH;

COOHa OUCOCHQ Uooom H N// N) S 00 a N r CH3 COCHa a i ooorr COCHs N/ N/ s Ha -a A Mei ll) 1 L /oo0c11 N CH; N

LII

It has previously been pointed out that the amide portion of the couplers described herein can be supplied by either a urethane or an isocyanate. Although both of these components react with about equal facility, the urethaues are preferred because they are more readily procurable. ing formulae:

and

These reactants are illustrated by the follow- R1N=C=O wherein R has the values as given above under Formula I and R represents a lower alkyl group, i.e., methyl, ethyl, propyl, etc. Typical structures contemplated within the confines of Formulae IIIa and Hlb can be depicted as follows:

lTI-COOEt IIICOOEt H H i miss N-OOOEI:

I N-COOEt y Me N-COOEt I NCOOEt NCOOEt N-OOOEt I O COOEt I COOEt H:CO

I N-COOEt NC O OMe I Me- NC O O E t 11 H C-O NCO NCO I I OMe C1 C1 Noo NC NC 0 NC 0 NC 0 NC 0 -01 o1 oiOol I I OMe 01 5015 31 NC 0 NC 0 NC 0 NC 0 C1 C1 Cl C1 C1- C1 B1 I I 01 ll Br NC 0 NC 0 NC 0 NC 0 F ]Cl 1 I I EI; NCO O In general, the beta-keto amides as described herein can be produced under a wide variety of conditions. In fact, it has been my finding that it is only necessary to provide the prerequisite methylaryl ketone and aromatic isoeyanate or urethane derivative thereof. L1 other words, my method of synthesis is deemed to be limited only by the availability of supply of the above mentioned intermediates.

There may, of course, be instances when the use of certain intermediates such as sterically hindered aryliso cyanates or urethanes or metal aryiketones may give rise to a rather low yield of the beta-keto amide. However, such instances would manifestly be an exception and cannot be considered as seriously imposing any limitation to the reaction. It has been my experience, however, that even when working with a highly substituted intermediate, satisfactory yields of beta-keto amides can be obtained. As brought out in the various working examples and illustrations of formulae, the reaction is obviously one of wide extent.

In carryin out the reactions, I have found that excellent results ensue when the arylisocyanate or urethane thereof and the beta-methyl arylketone are brought together in an inert solvent at elevated temperature in the presence of a highly basic condensing agent, preferably an alkali metal alkoxide, such as sodium methoxide. As shown in the equation, the alkali metal alkoxide reacts with the aromatic isocyanate or urethane to form an intermediate precurser (shown in brackets) and it is this adduct which then undergoes condensation with the methyl aromatic ketone. As a consequence, 1 prefer to add the basic condensing agent to the isocyanate or urethane to form the above-mentioned adduct, after which the ketone is then introduced and forms the salt of the beta-keto amide. Acidificaton of the reaction mixture liberates the free or acid form of the beta-keto amides which can then be readily purified by the usual techniques.

The solvent medium for carrying out these reactions is desirably an inert solvent such as the aromatic hydrocarbons, i.e., benzene, toluene, Xylene, mesitylene, etc. Chlorinated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene and trichlorobenzene are useful, especially if it is desired to run the reaction at a higher temperature, a condition which is made possible by the higher boiling points of these chlorinated solvents. Other inert media include tertiary heterocyclic bases such as pyridine, quinoline, and other tertiary amines exemplified by dimethyl aniline, diethyl aniline, dipropyl aniline and the like. The choice of the solvent is mainly determined by the reaction conditions such as temperature and solvent properties needed to effect dissolution of the reacting components. It is deemed to be evident that the choice of the solvent is a matter which falls within the routine knowledge of the skilled artisan in the organic chemical field.

It has been my experience that a highly basic condens ing agent is preferred in efiecting formation of the betaketo amides from the isocyanate or methane thereof and the methyl aromatic ketone. For this purpose I have found that the alkali metal alkoxides are eminently suitable and because they are readily obtainable, sodium methoxide or ethoxide is recommended. However, other, though lesser known, basic condensing agents can be employed and in this connection mention is made of the alkali metal salts of triphenylmethyl, lithium alkyl, lithium aniline and the like. Apparently, the only prerequisite in selecting a basic condensing agent is that it be sufficiently basic to form the above-described adduct of the arylisocyanate or urethane derivative thereof.

In the following examples are illustrated various ramifications of the new method for preparing beta-keto amides of the type commonly used in color photography. However, these examples are given by way of illustration only and are not to be construed as limiting the scope and extent of the invention except as necessitated by the appended claims.

EXAMPLE 1(a) 2-Benz0ylacelanilide Into a 250 ml. round-bottom flask equipped with a stirrer and reflux condenser were placed 100 ml. of dry xylene and 16.5 g. (0.1 mole) of phenyl urethane. To the stirred solution, 5.4 g. (0.1 mole) of commercial sodium methoxide was then added and the mixture heated on a steam bath for five minutes to complete conversion 12 EXAMPLE 2 2-(Z-Methoxybenzoyl)Acetanilide EXAMPLE 3 2-(4,7-DimethoxyJ-Naphth0yl)Acezanilide In this case the acetophenone of the first example was replaced by 0.1 mole of methyl 4,7-dimethoxy-1-naphthyl ketone and the reaction carried out in accordance with the procedure of the first example. The yield of product melting at 155156 C. approximated that of the first example.

EXAMPLE 4 2-(4-Chl0r0benz0yl)Acetanilide Following the procedure of Example 1, 0.1 mole of phenyl urethane was condensed with 0.1 mole of parachloroacetophenone. After purification, a product corresponding to the above formula was obtained which melted at 137-138 C.

EXAMPLE 5 4,4 '-Bis(Z-Benzoylacezanilide) to the sodium adduct. (This was indicated by the formation of a thick slurry.) The steam bath was then replaced by a heating mantle and 12.0 g. (0.1 mole) of acetophenone were added to the reaction mixture. After heating at reflux with stirring for 1-2 hours, the reaction mixture was cooled and poured into about 200 m1. of ether. The white sodium salt was'collected by filtration and washed with ether. The dry solids were then dissolved in 250 ml. of hot water, treated with charcoal and filtered. The filtrate was cooled and acidified with hydrochloric acid. An oil formed which soon solidified. The product was purified by crystallization from aqueous methanol. The. melting point of the purified product was 105107 C. (Mixed MP. with an authentic sample of benzoyl acetanilide was 106108 C. The infrared spectra of the two samples were identical.)

EXAMPLE 1 (b) Z-Benzoylacetanilide In this preparation, the solvent was anhydrous pyridine instead of xylene as used in Example 1(a). The procedure and results paralleled those of the first example.

EXAMPLE 1(0) In this preparation, an equivalent of phenyl isocyanate was used in place of phenyl urethane. The procedure and results paralleled those of Example 1(b).

2-(4-Cyan0benz0yl)Acetanilide By substituting paracyanoacetophenone for the unsubstituted structure of the first example, there was obtained a comparable yield of the corresponding para-cyanobetaketo amide corresponding to the above structure.

EXAMPLE 7 2- (4-Diethylaminobenz0yl)Acetanilide In this instance, equal molecular proportions of paradiethylamino acetophenone and phenyl urethane were reacted under conditions as set forth in the first example. The yield of beta-keto ester amide corresponding to the above formula approximated the yield as obtained in the first example.

EXAMPLE 8 2-(] -Naphthyl )-4-Phenylacetanilide 2- (4-F l uorobenzoyl -N -1 -N aphthylacetamide In this case the acetophenone derivative was the parafluoro configuration and the urethane was naphthyl urethane. The reaction in general proceeded along the same lines as enunciated in Example 1.

EXAMPLE 10 4- [2-(4-Eth0xybenzoyl)Acetamido]Pyridine I ETO Equal molar quantities of paraethoxy acetophenone and pyridine-4-urethane were condensed using reaction conditions as spelled out in Example 1. In general, the yield fell in the same neighborhood as obtained for the structures given in the earlier examples.

EXAMPLE 1 l 2- (4-Phenylbenz0yl)Acelanilide Using paraphenyl acetophenone and phenyl urethane, there was obtained a beta-keto anilide corresponding to the above structure. The procedure and yield generally corresponded to those of the previous examples.

EXAMPLE 12 4 -F luoro-Z- -M ethoxy-Z-T heonyl Acezanilide S-methoxy methyl-Z-theonyl ketone and parafluorophenyl urethane were combined in equal molecular portions following the procedure enunciated in Example 1. In general, the results and yield approximately those of the first example.

EXAMPLE 13 2-(4-Cyan0benz0yl) -3'-Flu0r0acetanilide In this example, paracyanoacetophenone was combined with metafluorophenyl urethane in equal molecular proportions to yield a beta-keto amide configuration of which is represented by the above formula. The yield approximated that obtained in Example 1.

EXAMPLE 14 2,3',5',6'-Tetramethyl-2-(4-Phenylbenz0yl)Acetanilide Me Me I I Me Me In this example, 1 equivalent of paraphenyl acetophenone and l equiavlent of 2,3,5,6-tetramethyl urethane was reacted under conditions spelled out in Example 1. In general the results and yield approximated those of the earlier examples.

I claim:

1. A process of preparing a beta-keto amide of the following formula:

R CCH2CNR1 t r wherein R and R are each selected from the class consisting of an aromatic ring, thiazolyl, methylthiazolyl, thienyl, benzothiazolyl, pyridyl, furyl, quinolyl and quinoxalinyl, which comprises heating in a substantially anhydrous inert solvent in the presence of a highly basic condensing agent containing an alkali metal atom a methyl aryl ketone of the following formula:

wherein R has the values as above designated with a compound selected from the class represented by the following formulae:

wherein R has the values as above designated and R represents a lower alkyl group, whereby is formed a complex of the basic condensing agent with the beta-keto amide, acidifying the complex to produce the free betaketo amide.

2. A process according to claim 1 wherein R and R are aromatic.

3. A process according to claim 1 wherein the inert solvent is xylene.

4. The process according to claim 1 wherein the inert solvent is pyridine.

5. A process according to claim 1 wherein the basic condensing agent is an alkali metal alkoxide.

6. A process of preparing a beta-keto amide of the following formula:

containing an alkali metal atom with a compound selected from the class represented by the following formulae:

wherein R has the values as above designated and R represents a lower alkyl group and treating the resultant 15 16 adduct which contains an alkali metal atom with amethyl 9. The process according to claim 6 wherein the inert aryl ketone of the following formula: solvent is pyridine.

10. A process according to claim 6 wherein the basic condensing agent is an alkali metal alkoxide. 0 5 11. A process according to claim 6 wherein the heatwherein R has the values as above designated, whereby ing i i d out t steam bmh temperature is formed a complex of the basic condensing agent with the beta-keto amide, and acidifying the complex to pro- R fer n s Cited in the file of this patent duce the free beta'keto'amlde- Comanducci et al.: Chemical Abstracts, vol. 16, page 7. A process according to claim 6 wherein R and R 10 3476 (1922) are aromatlc- Kocwa: Chemical Abstracts, vol. 31, pages 18034 8. A process according to claim 6 wherem the inert (1937) solvent is Xylene. 

1. A PROCESS OF PREPARING A BETA-KETO AMIDE OF THE FOLLOWING FORMULA: 